Nitric oxide inhibits tumor necrosis factor-α-induced apoptosis by reducing the generation of ceramide

Céline De Nadai, Piero Sestili, Orazio Cantoni, Jean Philippe Lièvremont, Clara Sciorati, Rico Barsacchi, Salvador Moncada, Jacopo Meldolesi, Emilio Clementi

Research output: Contribution to journalArticlepeer-review

Abstract

Apoptosis triggered by death receptors proceeds after defined signal- transduction pathways. Whether signaling at the receptor level is regulated by intracellular messengers is still unknown. We have investigated the role of two messengers, ceramide and nitric oxide (NO), on the apoptotic pathway activated in human monocytic U937 cells by tumor necrosis factor-α (TNF-α) working at its p55 receptor. Two transduction events, the receptor recruitment of the adapter protein, TRADD, and the activation of the initiator caspase, caspase 8, were investigated. When administered alone, neither of the messengers had any effect on these events. In combination with TNF-α, however, ceramide potentiated, whereas NO inhibited, TNF-α-induced TRADD recruitment and caspase 8 activity. The effect of NO, which was cGMP- dependent, was due to inhibition of the TNF-α-induced generation of ceramide. Our results identify a mechanism of regulation of a signal- transduction pathway activated by death receptors.

Original languageEnglish
Pages (from-to)5480-5485
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number10
DOIs
Publication statusPublished - May 9 2000

ASJC Scopus subject areas

  • Genetics
  • General

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